Cytokines such as TNF-α (tumor necrosis factor-α), IL-1 (interleukin-1) and the like are biological substances produced by various cells such as monocytes, macrophages and the like in response to cellular stress such as infection and the like (Koj, A., Biochim. Biophys. Acta, 1317, 84-94 (1996)). These cytokines play an important role in immune reactions when they are present in an appropriate amount, while it is believed that excess. production thereof is related to a lot of inflammatory diseases (Dinarello, C. A., Curr. Opin. Immunol., 3, 941-948 (1991)). A p38 MAP kinase cloned as a homologue of a MAP kinase is concerned with control of the production of these cytokines, and with a signal transfer system coupled with a receptor, so inhibition of a p38 MAP kinase provides a possibility of a remedy for inflammatory diseases (Stein, B., Anderson, D., Annual Report in Medicinal Chemistry, Bristol, J. A. (ed.), Academic Press, 31, pp. 289 to 298, (1996)).
As examples having such a p38 MAP kinase inhibiting activity, imidazole derivatives are described in JP-A 7-50317 (WO 93/14081) and oxazole derivatives are described in JP-A 9-505055 (WO 95/13067), respectively.
On the other hand, as a thiazole-based compound, the following compounds, etc. are known.
1) 1,3-thiazole derivatives of the formula:
wherein R1 represents a cycloalkyl group, a cyclic amino group, an amino group optionally having one or two lower alkyls, phenyls, acetyls or lower alkoxycarbonylacetyls as a substituent, an alkyl group optionally having hydroxyl, carboxyl or lower alkoxycarbonyl as a substituent, or a phenyl group optionally having carboxyl, 2-carboxyethenyl or 2-carboxy-1-propenyl as a substituent, R2 represents a pyridyl group optionally having a lower alkyl as a substituent, and R3 represents a phenyl group optionally having a lower alkoxy, lower alkyl, hydroxyl, halogen or methylenedioxy as a substituent, or a salt thereof, having analgesic, antipyretic, anti-inflammatory, antiulcer, thromboxane A2 (TXA2) synthase inhibitory, and antithrombotic activities (JP-A No. 60-58981).
2) 1,3-thiazole derivatives of the formula:
wherein R1 represents an alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, heterocyclic group having carbon as a connecting moiety, or amino group, R2 represents a pyridyl group optionally substituted with an alkyl group, and R3 represents a phenyl group optionally having a substituent, or a salt thereof, having analgesic, antipyretic, anti-inflammatory, antiulcer, TXA2 synthase inhibitory, and antithrombotic activities (JP-A No. 61-10580).
3) 1,3-thiazole derivatives of the formula:
wherein R1 represents an alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, heterocyclic group having carbon as a connecting moiety, or amino group, R2 represents a pyridyl group optionally substituted with an alkyl group, and R3 represents an aryl group optionally having a substituent, or a salt thereof, having analgesic, antipyretic, anti-inflammatory, antiulcer, TXA2 synthase inhibitory, and antithrombotic activities (U.S. Pat. No. 4,612,321).
4) Compounds of the formula:
wherein R1 represents phenyl optionally having a substituent, R2 represents a C1-6 alkyl or (CH2)nAr (n is 0 to 2, and Ar is phenyl optionally having a substituent), R3 represents hydrogen or C1-4 alkyl, R4 represents hydrogen, C1-4 alkyl or the like, R5 represents hydrogen or C1-4 alkyl, and R6 represents hydrogen, C1-4 alkyl or the like, or a salt thereof, having a gastric acid secretion inhibitory activity (JP-A No. 7-503023, WO 93/15071).
5) Compounds of the formula:
wherein R1 represents pyridyl or the like, R2 represents phenyl or the like, R3 and R4 represent hydrogen or methyl, R5 represents methyl or the like, and R6 represents hydrogen, methyl or the like, or a salt thereof, which are an anti-inflammatory agent and antiallergic agent (DE-A-3601411).
6) Compounds of the formula:
wherein R1 represents a lower alkyl substituted with a halogen, R2 represents pyridyl or the like, and R3 represents phenyl or the like, or a salt thereof, having anti-inflammatory, antipyretic, analgesic and antiallergic activities (JP-A No. 5-70446).
7) Thiazole compounds of the formula:
wherein R represents a lower alkyl group; lower haloalkyl group; lower hydroxyalkyl group; lower alkoxy lower alkyl group; aralkyloxy lower alkyl group or the like, R1 represents a cycloalkyl group optionally substituted with a lower alkyl group and the like, and R2 represents an aryl group optionally having a substituent, or the like, or a pharmaceutically acceptable salt thereof, having a TNF-α selective production inhibitory activity and/or IFN-γ production inhibitory activity (JP-A No. 11-49762).
There is a strong need to develop compounds having an excellent p38 MAP kinase inhibitory activity, TNF-α production inhibitory activity, adenosine receptor antagonizing activity and PDE IV inhibitory activity.